V. Cellular basis of action of GI peptides. V.A. Ability of cholecystokinin (CCK) to stimulate P125 focal adhesion kinase (P125-FAK) and paxillin tyrosine phosphorylation (TYR PHOSP). Recent studies demonstrate that some G-protein coupled receptors may signal through tyrosine phosphorylation of P125-FAK and paxillin similar to many oncogenes, growth factors and bioactive lipids, particularly in mediating their effects on cellular growth and motility. In two studies we investigated in detail the cellular basis for the ability of the neuropeptide cholecystokinin [CCK] to cause these changes in rat pancreatic acini. We found CCK causes a rapid TYR PHOSP of both proteins and that it is mediated by both activation of high and low affinity CCKA receptor states. We found that it is mediated by a phospholipase C-dependent and -independent pathway, that the integrity of the actin-cytoskeleton is essential for activation and that the small GTP binding protein, p21-rho at least partially mediates CCK's ability to cause TYR PHOSP of these two proteins. V.B. Ability of gastrin-releasing peptide receptor (GRP-R) to couple to both adenylate cyclase and PLC. In some cell lines GRP-R couples to both of these cascades whereas in others it does not. This study demonstrated that GRP-R activation in dispersed cells from normal tissues from three different species and a human tumoral lung cancer cell line, does not couple to adenylate cyclase, whereas in Swiss 3T3 cells it does. This difference in coupling is at least partially due to coupling to an adenylate cyclase subtype whose activation is regulated by protein kinase C.